These values are found in Table 3. Table 3. Radiologic findings.
Gd-enhancinglesionsMean (SD)n1088898777Baseline0.0(0.0)0.1(0.4)0.1(0.4)0.5(1.1)0.0(0.0)0.0(0.0)0.0(0.0)0.1(0.4)0.0(0.0)Day 600.0 (0.0)0.4 (0.7)0.0 (0.0)bC0.1 (0.4)0.0(0.0)0.0(0.0)c0.0(0.0)b0.0(0.0)0.0(0.0)0.0(0.0)dChange to Day?600.0(0.0)0.3 (0.7)C0.5 (1.1)0.0(0.0)0.0(0.0)0.0(0.0)C0.1 (0.4)0.0(0.0)Brain-volumeChange (%)Mean (SD) n 300087767Change to Day?600.09(0.47)NDNDND0.04(0.35)0.00(0.36)C0.06(0.36)0.05(0.34)C0.07(0.58)NAA:Cr ratioMean (SD) n 1088798777Baseline1.38(0.19)1.51(0.32)1.41(0.24)1.40(0.19)1.53(0.23)1.41(0.19)1.38(0.20)1.33(0.21)1.52(0.24)Day 601.41(0.21)1.51(0.30)1.36(0.35)1.45(0.11)1.52(0.17)1.44(0.16)1.44(0.28)1.33(0.23)1.65(0.51)Change to Day?600.02(0.10)C0.05(0.10)C0.02(0.12)0.05(0.13)C0.03(0.13)0.06(0.16)0.06(0.20)C0.01(0.09)0.20(0.28) Open in a separate window The table indicates that there were no meaningful differences in changes from baseline to Day 60 in radiologic findings between Salinomycin sodium salt the Salinomycin sodium salt placebo and any treatment group. rHIgM22: monoclonal recombinant human antibody IgM22; Gd: gadolinium; NAA: N-acetylaspartate; Cr: creatine. PK rHIgM22 exhibited a dose-proportional Cmax and AUC0C over the range of doses tested in this trial. the 21 participants of the extension cohort. Conclusions Single doses of rHIgM22 were well tolerated and exhibited linear PK, and antibody was detected in the CSF. Keywords: Clinical trial, demyelination, disease-modifying therapies, multiple sclerosis Introduction The mainstay of current treatments for relapsingCremitting multiple sclerosis (MS) is the use of immunomodulatory and immunosuppressive drugs. These drugs have reduced the annualized relapse rate but the disease can continue to progress and disabilities accumulate. Even in extreme cases of immunoablation with reconstitution of the immune system by autologous hematopoietic stem cell transplantation, repair of pre-existing damage is limited.1 Therefore, attention in drug development for MS has been drawn to the potential for reparative, remyelinating therapies.2C4 A number of small-molecule drugs that are approved for other indications have been identified, using preclinical screening techniques, that appear to promote remyelination in animal models and some of these have completed early-stage clinical trials5 (see also NCT02040298). In addition, a monoclonal antibody that neutralizes the myelination inhibitory factor LINGO-1 has been advanced through Phase 2 clinical trials in optic neuritis and MS6,7 (see also NCT01721161 and NCT01864148). Another monoclonal antibody that has been shown to promote remyelination in animal models is usually recombinant human immunoglobulin (Ig)M22 (rHIgM22).8C10 This antibody was identified and cloned from a patient with Waldenstroms macroglobulinemia. Salinomycin sodium salt It binds to a prevalent antigen expressed only in the central nervous system (CNS) white matter. Although the complex, proteo-lipid antigen recognized by this antibody and the pathways modulated by its binding have not been fully defined, it has been shown capable of promoting remyelinating activity in cellular systems and several animal models of demyelination.11 Herein we report around the safety, tolerability, pharmacokinetics (PK) and CNS penetration of rHIgM22 in a first-in-human, randomized, placebo-controlled, Phase 1, single ascending-dose clinical trial in individuals with clinically stable MS. Methods Study design, consent and approvals This was a Phase 1, multicenter, double-blind, randomized, placebo-controlled, dose-escalation study designed to evaluate safety, tolerability, PK, immunogenicity (reported elsewhere), and exploratory pharmacodynamics of single intravenous (IV) administrations of rHIgM22 in patients with clinically stable MS. The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice and applicable regulatory requirements. The protocol was approved by the institutional review boards and all participants gave written informed consent. The Trial Registration Identifier is usually NCT01803867 (www.clinicaltrials.gov). Eligibility, enrollment, dosing Rabbit polyclonal to TGFB2 and follow-up Following informed consent, individuals with a diagnosis of MS (McDonald 2010 criteria12) and between the ages of 18 and 70 years, inclusive, with no evidence of active disease or medication changes within the preceding three months, were enrolled at one of 17 centers in the United States (US). Key exclusion criteria were various medical conditions or medication usage that would potentially impair safe participation or interpretation of trial results or initiation of various disease-modulating therapies within prespecified intervals, a history of infusion reactions to biologics or any contraindication to brain magnetic resonance imaging (MRI). Patients were enrolled and completed all visits between April 2013 and October 2014. See https://clinicaltrials.gov/ct2/show/NCT01803867. Initially, individuals were enrolled in one of five successive dose-escalation cohorts in which the first two patients in each cohort were randomized, one to receive placebo and one to receive active drug. Following a review of clinical and radiologic safety findings at two weeks, in the absence of any dose-limiting toxicity, the next eight individuals were randomized to placebo (one) or active drug (seven). Following a review of all preceding safety data, in the absence of any dose-limiting toxicity, the next higher-dose cohort was similarly enrolled. In this fashion, 51 patients were enrolled in the five dose levels spanning 0.025 to.
